Cell therapeutics

Cell and gene therapies are innovative treatment methods that enable curative approaches for severe, previously incurable diseases. In addition to hematopoietic stem cell transplantation, therapies using genetically modified cells have also been approved as advanced therapy medicinal products (ATMPs) in the USA and Europe in recent years. These CAR-T cell therapies, in which the patient's own T cells are modified with chimeric antigen receptors (CAR), have so far been used almost exclusively in cancer therapy.

CAR T-cell therapy

Approved CAR-T cell therapeutics, as well as the vast majority of new CAR-T cells in development, are based on the stable genetic modification of patients' own cells using viral vectors. Since CAR-T cell therapy is a very young method, the long-term consequences due to off-target effects, for example, have been scarcely studied. Furthermore, persistent CAR-T cells cause severe side effects. An alternative to stable modification is the temporary modification of cells by means of a messenger RNA (mRNA) coding for the CAR protein.

A transfer of the therapeutic approach of CAR-T cell therapy to infectious diseases, autoimmune diseases and fibrosis is state of the art in current research. In fibrotic diseases, the stromal-immune cell axis plays a crucial role. Therefore, activated misdirected fibroblasts represent an important target for therapies. Stably generated CAR-T cells against activated fibroblasts have been successfully used to reduce fibrosis in preclinical studies.

Treatment of immune-mediated diseases with CAR-T cell therapeutics

The goal is to develop transient CAR cell therapeutics for the treatment of immune-mediated diseases. For this purpose, new mRNA techniques and nanotransporter systems will be developed. In this way, CAR-T cells against activated fibroblasts will be generated in an establishment project. Human 3D cell culture and tissue models of fibrosis as well as a novel imaging platform will be used for functional testing. Another goal is to transfer the technology to natural killer (NK) cells to develop donor-independent CAR cell therapies.

How will this development contribute to improving the status quo?

The platform of excellence will develop mRNA-based CAR cell therapeutics that have an enhanced safety profile. This will create a transient ATMP approach for the treatment of fibrotic diseases. In order to meet the future demand for CAR cell therapies, the transition from autologous (patient's own) to allogeneic (donor's own) products will be promoted, so that as many patients as possible can be treated with one product batch.

Bringing together complementary competencies

Fraunhofer IZI leads the competence platform and the molecular biological ATMP development. The platform is supported by Fraunhofer IAP-CAN with its expertise in tailor-made nanotransporter systems and by Fraunhofer ITEM with its expertise in RNA therapeutics, in silico analytics and human in vitro and ex vivo fibrosis models.  For ATMP functional testing, IZI and Fraunhofer ISC (TLZ-RT) combine their cell analytical expertise in the field of 3D cell culture and tissue models as alternatives to animal testing. 

Outlook

The competence platform should enable the Fraunhofer Society to compete internationally in the field of cell therapeutics for immune-mediated diseases. If the establishment project is successful, further ex vivo models of fibrotic tissues will be used for testing CAR cells in collaboration with Fraunhofer ITEM. At the same time, the platform will be expanded in the medium term to include other cell therapy modes of action (e.g., T cell receptor-modified cells) as well as other target indications (e.g., osteoarthritis).

Future research needs include in vivo testing of the developed cell therapeutics. In parallel, a linkage with the other competence platforms of the CIMD is aimed at. To realize this, the complementary and reinforcing effects of a combination therapy of cell therapeutic (IZI) and RNA-based (ITEM) strategies in models of fibrotic disease patterns will be explored.